Alzheimer’s disease (AD) is one of the most common causes of dementia in the elderly, and by 2050 it is expected that this pathology will affect more than 100 million people. Brain barriers are extremely relevant for the clearance of amyloid-beta peptide (a-beta), whose brain accumulation is the best known pathological hallmark of AD. The blood-cerebrospinal fluid barrier, formed by the choroid plexus (CP) epithelial cells, is a unique structure that not only provides mechanical protection to the brain but also buffers extracellular fluids, supplies nutrients and participates in brain signaling. Recent studies have highlighted the importance of CP in a-beta clearance, and several evidences indicate that age-related decline in sex hormones (SH) significantly contribute to AD risk in men and women, due to their action as negative regulators of a-beta levels. In AD, the CP develops abnormalities that may alter synthesis, secretion and transport of proteins and other molecules, including a deficient clearance of a-beta, which may be related to mitochondrial activity deficits, oxidative stress, morphological changes, and a-beta scavenger’s impairment, resulting in brain a-beta accumulation. This study aimed at understanding how aging and hormonal background might modulate these biological processes on CP. Real-time PCR was used to analyze the gene expression of important a-beta scavenger’s (transthyretin, apolipoprotein-J and gelsolin) in CP explants treated with a-beta at different stages of life (newborns, young, and adults). Moreover, in adult animals, differences in the male and female CP response to a-beta were also assessed. To understand the role of SH in a-beta accumulation, Z310 cells (CP cell line) were pre-treated with estradiol (E2) or dihydrotestosterone (DHT) and incubated with a-beta to determine a-beta cellular accumulation by immunocytochemistry, and reactive oxygen species (ROS) production using DCFH-DA staining followed by confocal microscopy (live imaging). We found that TTR, ApoJ and Gls gene expression levels decline not only in an age-dependent manner, but also in a gender-dependent manner. CP explants from adult females, and treated with a-beta, showed a severe decrease in the levels of a-beta scavenger’s in comparison with adult males. These observations may be related with the reported major susceptibility of women to develop AD than men, due to a more accentuated decline in SH with aging. The treatment with SH reduced a-beta internalization and oxidative stress in Z310 cell line, and this hormonal-dependent reduction was confirmed when the antagonists for E2 and DHT (ICI 182,780 and flutamide, respectively) were used. These findings suggest that the hormonal background regulates several neuroprotective mechanisms against a-beta toxicity in CP, in an age and sex-dependent manner, which may be an important pathway preventing a-beta accumulation, providing a new potential therapeutic target to prevent scavenger’s impairment and to reduce oxidative stress and apoptosis in Alzheimer’s disease development.